Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) determining the molecular basis of TSE strains, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) development of effective therapeutic TSE agents, 4) identifying the earliest events which occur during TSE infection, and 5) studying the regions of PrP involved in the species-specific formation of PrP-res. In the last year, we have begun to study the earliest events that occur following exposure of cells to TSE infectivity. We have demonstrated that, although all cell types exposed to TSE agents can support PrP-res formation, only some are actually capable of making PrP-res persistently and becoming chronically infected. We have also developed new systems to study PrP fibril formation, a process that may be important in acquired and familial forms of TSE disease. Finally, we have initiated in vivo experiments to study the efficacy of PrP peptide vaccine approaches to TSE disease.